Multiple sclerosis (MS) is the leading cause of neurological non- traumatic disability for young adults in Norther America. This revised Program Project application is based on the hypothesis that the inflammatory destructive process in MS patients is active from disease onset and that progressive neurologic disability is a late complication of accumulated, irreversible tissue injury. The program consists of three related projects and one core. Project 1: Chemokines and chemokine receptors in multiple sclerosis (RM Ransohoff, PI) will address the hypothesis that specific chemokines and receptors are significantly involved in central nervous system (CNS) inflammation during MS. To define molecular targets for therapy, we will focus on chemokines and receptors expressed by T cells and mononuclear phagocytes in MS. PROJECT 2: Axonal pathology in multiple sclerosis (BD Trapp) is based on the hypothesis that axonal pathology is a primary contributor to neurological deficits in MS patients and should be considered as a therapeutic target. Axonal pathology will be characterized in spinal cords of patients dying from MS; in rats subjected to spinal cord transection and in mice with experimental autoimmune encephalomyelitis (EAE). Data will be correlated with biochemical measures of N-acetyl aspartate of N-acetyl aspartate, a reflection of axonal injury. In aim 4, oligodendrocyte progenitors in MS brain will be characterized, because chronic deprivation of the trophic support of myelin is responsible in part for anatomic interruption of axons in MS lesions. Project 3: Monitoring brain atrophy during the course of multiple sclerosis (RA Rudick) will test the hypothesis that brain atrophy will be a practical, sensitive and relevant surrogate marker of the underlying disease process. Recent studies indicate that brain atrophy can be measured from the early stages of MS in relapsing-remitting patients. Project 3 will address the rate and temporal pattern of brain atrophy in MS patients, and will establish relationships between brain atrophy and clinical disability in MS patients. The relation between brain atrophy on MRI and various additional MRI lesion types will be established, and we will perform MR/pathological correlations from scans performed at the time of autopsy during our tissue acquisition protocol. Core: Tissue acquisition, biostatistics, administration (RA Rudick) will establish, maintain and distribute for projects a unique resource of MS autopsy tissue, histological and post- mortem imaging data. This core will provide data analysis/management and administrative support for projects. This research program will directly impact monitoring and treatment of MS.